Project Summary Despite advances in hypertension prevention and treatment research, its prevalence is high and increasing, while the proportions of hypertensive patients who are aware, treated, and controlled are low, especially in low- and middle-income countries (LMIC). We propose to: assess the needs, barriers, and knowledge gaps of hypertension control programs in the national health care systems of the Central America 4 region LMIC (CA- 4: Guatemala, Honduras, El Salvador, and Nicaragua); conduct a cluster randomized trial to test the effect of a multilevel and multicomponent intervention program on blood pressure (BP) control among Guatemalan hypertensive patients; and evaluate the adaptability, feasibility, fidelity, and sustainability of implementing the program in the primary health care systems of the CA-4 region. We will conduct formative research to assess the needs of system-wide intervention programs, barriers and facilitators of BP control strategies, and knowledge gaps about implementation for improving hypertension control in the CA-4 health care systems. The proposed trial will recruit 1,770 study participants from 32 primary care districts (55 patients aged ?22 years with uncontrolled hypertension/district) within a subnational primary care network managed by the Guatemalan Ministry of Health. Sixteen health districts will be assigned to an 18-month multicomponent intervention, which includes protocol-based treatment using: a standard blood pressure (BP) management algorithm, team-based collaborative care, BP audit and feedback, home BP monitoring, and health coaching on antihypertensive medication adherence and lifestyle modification, and 16 to usual care. The study will use an effectiveness-implementation hybrid type 2 design to test effectiveness of the multicomponent intervention program. BP and other indicators will be measured at baseline and at months 6, 12, and 18. The primary clinical outcome is the difference in the proportion of patients with controlled BP (<140/90 mmHg) between the intervention and control groups at 18 months. The secondary outcome is net change in systolic and diastolic BP from baseline to 18 months. Implementation outcomes (acceptability, adoption, appropriateness, feasibility, fidelity, reach, and sustainability) will be measured every 6 months. The RE-AIM framework will guide the development, implementation, and assessment of the intervention, which will translate and adapt the Hypertension Control Program in Argentina that has been proven effective and feasible. We have assembled a multidisciplinary investigative team, which will collaborate with the public primary care network in Guatemala to conduct this implementation research project. The intervention and study outcomes are patient-centered, and patients, MOH provider-teams, and other stakeholders will be engaged at every step of the proposed study. We will disseminate the study findings and promote scale-up of the proven effective intervention program, which will generate urgently needed data on effective, adoptable, and sustainable intervention strategies aimed at reducing BP-related disease burden in CA-4 and other low-income settings.